This invention is directed to substituted phenol compounds; pharmaceutical compositions containing substituted phenol compounds; and methods of using such compounds and compositions to induce or maintain general anesthesia or sedation in a mammal. This invention is also directed to processes and intermediates useful for preparing substituted phenol compounds.
Propofol (i.e., 2,6-diisopropylphenol) is an injectable anesthetic used to induce and maintain general anesthesia and sedation. Because of its beneficial properties and ease of administration, propofol is widely-used for both human and veterinary applications.
One drawback of propofol is that it is retained in the body and metabolized relatively slowly. Therefore, patient recovery can be unpredictable and is often dependent on the total amount of propofol administered.
Accordingly, a need exists for novel anesthetic agents. In particular, a need exists for novel anesthetic agents having a predictable duration of action.
The present invention provides substituted phenol compounds and pharmaceutical compositions containing substituted phenol compounds, which compounds and compositions are useful for inducing and maintaining general anesthesia or sedation in a mammal. The substituted phenol compounds of this invention contain a reactive functional group which allows the compounds to be converted (i.e., hydrolyzed or metabolized) in vivo into an inactive derivative. Thus, the substituted phenol compounds of this invention have a predictable duration of action when administered to a patient.
Accordingly, in one of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of: 
wherein
R1 and R2 are each independently (C1-C8)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C8)alkyl;
L is selected from the group consisting of covalent bond and a hydrocarbylene group containing from 1 to about 12 carbon atoms and optionally containing from 1 to about 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; and
R3 is selected from the group consisting of xe2x80x94C(xe2x95x90O)ORa, xe2x80x94C(xe2x95x90O)SRa, xe2x80x94P(xe2x95x90O)(ORa)2, xe2x80x94C(xe2x95x90O)OCH2C(xe2x95x90O)N(Ra)2, and xe2x80x94C(xe2x95x90O)OC(xe2x95x90O)Ra wherein each Ra is independently selected from a hydrocarbyl group containing from 1 to about 20 carbon atoms and optionally containing from 1 to about 5 heteroatoms selected from the group consisting of halo, nitrogen, oxygen and sulfur;
or a pharmaceutically acceptable salt thereof.
In another of its composition aspects, this invention provides a compound of formula (V): 
wherein L is a covalent bond, methylene, or ethylene; and R3 is as defined herein;
provided when L is a covalent bond, R3 is not xe2x80x94C(xe2x95x90O)ORa wherein Ra is methyl, ethyl, 1,2-dibromoethyl, but-2-enyl, hexadecyl, stearyl, or benzyl; and
provided when L is ethylene, R3 is not xe2x80x94C(xe2x95x90O)ORa wherein Ra is methyl or stearyl;
or a pharmaceutically acceptable salt thereof.
In yet another of its composition aspects, this invention provides a compound of formula (X): 
wherein
R4 is (C1-C5)alkyl, (C2-C5)alkenyl, or (C2-C5)alkynyl;
R5 is (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8) cycloalkyl(C1-C6)alkyl; and
R6 is methyl;
or R5 and R6 together with the carbon atom to which they are attached form a (C3-8)cycloalkyl; and
Ra is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl, or (C3-C8)cycloalkyl.
The substituted phenol compounds and pharmaceutical compositions of this invention are useful for inducing or maintaining anesthesia or sedation in a mammal, such as a human or domesticated mammal.
Accordingly, in one of its method aspects, this invention is directed to a method for inducing or maintaining anesthesia or sedation in a mammal, comprising administering to a mammal an anesthesia or sedation-producing amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from formulae (I) or (II), or a pharmaceutically acceptable salt thereof.
The invention also provides substituted phenol compounds for use in medical therapy (e.g. for inducing or maintaining anesthesia or sedation). Additionally, this invention provides substituted phenol compounds for use in the manufacture of a medicament useful for inducing or maintaining anesthesia or sedation in a mammal (e.g. a human).
The invention also provides processes and intermediates disclosed herein that are useful for preparing substituted phenol compounds, or that are useful for preparing compositions comprising substituted phenol compounds.